Human Colon Cancer

结直肠癌是美国第三大发病率最高的癌症和癌症相关死亡原因。 MicroRNA是一类小的非编码RNA，与结直肠癌的发病机制和预后有关，但很少有研究探讨microRNA的种系突变与结直肠癌的风险和预后之间的关系。 因此，我们研究了位于10 q24基因座内的hsa-mir-608中的SNP与结直肠癌之间的关联。 一个由245例病例和446例对照组成的队列对rs 4919510进行基因分型。 非裔美国人GC基因型的频率（15%）显著高于白人（3%）对照组。 rs 4919510与结直肠风险之间无显著相关性（非裔美国人：OR（GC vs. CC）0.89 [95% CI，0.41-1.80]）（白人：OR（GG vs. CC）1.76 CI，0.48-6.39]）。 然而，我们确实观察到了与生存的关联。 GC基因型与高加索人死亡风险增加相关（HR（GG vs. CC）3.54（[95% CI，1.38-9.12]），与非裔美国人死亡风险降低相关（HR（GG vs. CC）0.36（[95% CI，0.12-1.07]）。 这些结果表明，rs 4910510可能与结直肠癌生存的方式依赖于race.Because慢性肠道炎症是结直肠癌的危险因素，我们假设，炎症介质的遗传变异，如甘露糖结合凝集素2（MBL 2），与结肠癌的易感性。在这里，我们报告了24个MBL 2单核苷酸多态性（SNP）和相应的单倍型与结肠癌风险的病例对照研究。该基因3 '非翻译区（UTR）中的4个SNP（rs 10082466、rs 2120132、rs 2099902和rs 10450310）与非裔美国人结肠癌风险增加相关。纯合变体相对于野生型的OR范围为3.17 [95%置信区间（CI），1.57-6.40]至4.51（95% CI，1.94-10.50），而由这四种变体组成的3 '-UTR区域单倍型的OR为2.10（95% CI，1.42-3.12）。rs 10082466的C等位基因表现出miR-27 a的结合亲和力，并且该等位基因与较低的MBL血浆水平和活性两者相关。我们发现，已知与中等和低MBL血清水平相关的5'分泌单倍型表现出与非裔美国人结肠癌风险增加相关，特别是由两种单倍型LYPA和LYQC驱动，相对于参考HYPA单倍型（LYPA：OR，2.60; 95%CI，1.33-5.08和LYQC：OR，2.28; 95%CI，1.20-4.30）。在高加索人中未观察到类似的相关性。总之，我们的研究结果支持MBL 2的遗传变异增加非裔美国人结肠癌易感性的假设。microRNAs在各种生理和病理生物学过程中发挥着重要作用，包括癌症。对于直肠癌，只有有限的数据可用于microRNA表达谱，而基本的基因组和转录组畸变已被牢固确立。因此，我们与托马斯里德合作，旨在全面绘制这种疾病的microRNA表达模式。实验设计：前瞻性收集了57例局部晚期直肠癌患者的肿瘤活检和相应的匹配粘膜样本。提取总RNA，随后建立所有患者的肿瘤和粘膜microRNA表达谱。使用半定量实时PCR验证所选microRNA的表达。 49种microRNA在直肠癌和正常直肠粘膜之间显著差异表达（log 2倍差异大于0.5，p小于0.001）。这些microRNA的预测靶点富集了以下KEGG通路：Wnt、TGF-β、mTOR、胰岛素、MAPK和ErbB信号传导。这49种microRNA中的13种似乎是直肠癌特异性的，并且先前未报道用于结肠癌：miR-492、miR-542- 5 p、miR-584、miR-483- 5 p、miR-144、miR-2110、miR-652*、miR-375、miR-147 B、miR-148 a、miR-190、miR-26 a/B和miR-338- 3 p。在临床影响方面，miR-135 b表达与116例患者的独立多中心队列中的无病生存期和癌症特异性生存期显著相关。 对直肠癌microRNAome的全面分析揭示了与直肠癌相关的新型microRNA和途径。这些信息有助于详细了解这种疾病。此外，miR-135 b的鉴定和验证可能有助于确定新的分子靶点和治疗开发途径。

Colorectal cancer is the third most incident cancer and cause of cancer-related death in the United States. MicroRNAs, a class of small non-coding RNAs, have been implicated in the pathogenesis and prognosis of colorectal cancer, although few studies have examined the relationship between germline mutation in the microRNAs with risk and prognosis. We therefore investigated the association between a SNP in hsa-mir-608, which lies within the 10q24 locus, and colorectal cancer. A cohort consisting of 245 cases and 446 controls was genotyped for rs4919510. The frequency of the GC genotype was significantly higher in African Americans (15%) compared to Caucasians (3%) controls. There was no significant association between rs4919510 and colorectal risk (African American: OR (GC vs. CC) 0.89 [95% CI, 0.41-1.80]) (Caucasian: OR (GG vs. CC) 1.76 CI, 0.48-6.39]). However, we did observe an association with survival. The GC genotype was associated with an increased risk of death in Caucasians (HR (GG vs. CC) 3.54 ([95% CI, 1.38-9.12]) and with a reduced risk of death in African Americans (HR (GG vs. CC) 0.36 ([95% CI, 0.12-1.07]). These results suggest that rs4910510 may be associated with colorectal cancer survival in a manner dependent on race.Because chronic intestinal inflammation is a risk factor for colorectal cancer, we hypothesized that genetic variants of inflammatory mediators, such as mannose-binding lectin 2 (MBL2), are associated with colon cancer susceptibility. Here, we report the association of 24 MBL2 single-nucleotide polymorphisms (SNP) and corresponding haplotypes with colon cancer risk in a case-control study. Four SNPs in the 3'-untranslated region (UTR) of the gene (rs10082466, rs2120132, rs2099902, and rs10450310) were associated with an increased risk of colon cancer in African Americans. ORs for homozygous variants versus wild-type ranged from 3.17 [95% confidence interval (CI), 1.57-6.40] to 4.51 (95% CI, 1.94-10.50), whereas the 3'-UTR region haplotype consisting of these four variants had an OR of 2.10 (95% CI, 1.42-3.12). The C allele of rs10082466 exhibited a binding affinity of miR-27a and this allele was associated with both lower MBL plasma levels and activity. We found that 5' secretor haplotypes known to correlate with moderate and low MBL serum levels exhibited associations with increased risk of colon cancer in African Americans, specifically as driven by two haplotypes, LYPA and LYQC, relative to the referent HYPA haplotype (LYPA: OR, 2.60; 95% CI, 1.33-5.08 and LYQC: OR, 2.28; 95% CI, 1.20-4.30). Similar associations were not observed in Caucasians. Together, our results support the hypothesis that genetic variations in MBL2 increase colon cancer susceptibility in African Americans.MicroRNAs play a prominent role in a variety of physiological and pathological biological processes, including cancer. For rectal cancers, only limited data are available on microRNA expression profiles, while the underlying genomic and transcriptomic aberrations have been firmly established. In collaboration with Thomas Reid, we therefore aimed to comprehensively map the microRNA expression patterns of this disease. Experimental design: Tumor biopsies and corresponding matched mucosa samples were prospectively collected from 57 patients with locally advanced rectal cancers. Total RNA was extracted, and tumor and mucosa microRNA expression profiles were subsequently established for all patients. The expression of selected microRNAs was validated using semi-quantitative real-time PCR. Forty-nine microRNAs were significantly differentially expressed (log2-fold difference greater than 0.5 and p less than 0.001) between rectal cancer and normal rectal mucosa. The predicted targets for these microRNAs were enriched for the following KEGG pathways: Wnt, TGF-beta, mTOR, insulin, MAPK, and ErbB signaling. Thirteen of these 49 microRNAs seem to be rectal cancer-specific, and have not been previously reported for colon cancers: miR-492, miR-542-5p, miR-584, miR-483-5p, miR-144, miR-2110, miR-652*, miR-375, miR-147b, miR-148a, miR-190, miR-26a/b, and miR-338-3p. Of clinical impact, miR-135b expression correlated significantly with disease-free and cancer-specific survival in an independent multicenter cohort of 116 patients. This comprehensive analysis of the rectal cancer microRNAome uncovered novel microRNAs and pathways associated with rectal cancer. This information contributes to a detailed view of this disease. Moreover, the identification and validation of miR-135b may help to identify novel molecular targets and pathways for therapeutic exploitation.